To address the Specific Aims of the Program Project we have assembled a talented team in PROJECT I (Polygenic Causes of Isolated or Non-Syndromic Congenital Diaphragmatic Hernia (CDH) will be Informed by Rare Monogenic CDH) headed by Principal Investigators Barbara Pober, MD, and Jay Wilson,MD. Dr. Wilson has conceived and nurtured one of the most impressive follow up clinics for patients with congenital diaphragmatic hernia which has served as a model for other clinics around the country. Its interdisciplinary nature provides a broad spectrum of care to address the needs of CDH survivors who often have severe bronchopulmonary dysplasia accompanied by feeding disorders caused by gastroesophageal reflux and contributing to continued lung injury, failure to thrive because of feeding difficulties, and associated hearing abnormalities and neurological disorders particularly in those patients with syndromic CDH. Dr. Wilson, in addition, has direct responsibilities for managing these patients while on extracorporeal membrane oxygenation (ECMO) and during their multiple surgical procedures directed toward repair of the diaphragm and other associated congenital anomalies. He works with a team of pediatric surgeons at the Children's Hospital Boston and Dr. Donahoe works with the team at the Mass General Hospital for Children. Virtually all of the patients at both sites have been enrolled into the study due to the generosity of their parents and their investment In finding the genetic causes of these anomalies. This has resulted In an approximately ninety percent accrual rate at both institutions over the course of this expanding grant. Dr. Barbara Pober, M.D., is one of the leading geneticists in the world in the study of CDH. She personally phenotypes all of the patients and enters them into a database which she designed with Danny Shaw at the Children's Hospital Boston, into which clinical data is entered. Her careful phenotyping is matched in the operating room by the very precise documentation of the location and the severity of the diaphragm defect by each surgeon to define the phenotype. Dr. Pober has worked with her colleagues all over the world;the professional regard with which she is held by her colleagues has lead to our successful accrual of informative multiplex families. She directly supervises the study coordinators based both at Children's and at Mass General Hospital for Children for appropriate ascertainment, collection of specimens and their proper disbursement to the Massachusetts General Hospital for the extraction of DNA, and the creation of lymphoblast or fibroblast cell lines. Dr. Pober works with Dr. Donahoe, the research fellows, and the Program Coordinator to direct the flow of specimens to appropriate laboratories and to collect, interpret, and integrate resulting data. Family pedigrees are drawn for each family with multiple affected patients with CDH and attempts are made to document if consanguinity is present. During the course of the present grant interval, strategies to examine singletons from consanguineous families have been devised so that regions showing identity by decent or loss of heterozygosity (LOH) are examined for concomitant copy number variants (CNVs). It Is thought that this coincidence of CNVs in regions of LOH occurs in about ten percent of the consanguineous singletons which makes this approach worthwhile to undertake. Caroline Coletti, M.S., our program coordinator, maintains the flow of specimens via the administration core and reports results between the multiple sites working together to achieve the goals of this Program Project. She and Dr. Donahoe will work with the Principal Investigators of each Project I, II, and III, and the Core Directors to select the appropriate platform for study and to collect data for subsequent storage and interpretation. They will meet every two weeks on site or by video conferencing and plan External Advisory Committee input and evaluation. They will also plan manuscripts, progress reports, and grant renewals.